Monday, March 23, 2015

Quantifying the "central dogma"

There was a short article in a recent issue of Science that caught my eye. The title was "Statistics requantitates the central dogma."

As most Sandwalk readers know, The Central Dogma of Molecular Biology says,
... once (sequential) information has passed into protein it cannot get out again (F.H.C. Crick, 1958)
The central dogma of molecular biology deals with the detailed residue-by-residue transfer of sequential information. It states that such information cannot be transferred from protein to either protein or nucleic acid. (F.H.C. Crick, 1970)
You might wonder how you can quantify the idea that once information gets into protein it can't flow back to nucleic acids. You can't, of course.

The authors are referring to the standard scheme of information flow from DNA to RNA to protein. This is often mistakenly referred to as the Central Dogma by those scientists who haven't read the original papers. In this case, the authors of the Science article are asking whether the levels of protein in different cells are mostly controlled at the level of transcription, translation, mRNA degradation, or protein degradation.

The question might seem a little silly since the answer is "transcription." When a gene is not transcribed there is no protein and when it is transcribed you get protein. This has been known since Jacob and Monod. There are some exceptions but regulation of gene expression is predominantly at the level of transcription initiation.

So, what's the problem? The problem is that many scientists have been looking at the steps beyond just the presence or absence of protein in different cells. They've been looking at the amounts of a given protein in different cells to see if the quantitative variation is due to different levels of transcription or different levels of translation, or something else.

Surprisingly, recent papers have claimed that once a gene is transcribed the final levels of protein are mainly regulated at the level of translation. The purpose of this little review is to point point out that recent work has called those result into question. Apparently the earlier papers didn't handle their statistics correctly!

New experiments, and a reevaluation of previous experiments, suggest that transcription is the main process that regulates protein levels in different cells. This is not a surprise.

Now that sanity has been restored, do you think we could teach these scientists about the Central Dogma?

Not holding my breath.


Crick, F.H.C. (1958) On protein synthesis. Symp. Soc. Exp. Biol. XII:138-163.

Crick, F. (1970) Central Dogma of Molecular Biology. Nature 227, 561-563. [PDF file]

12 comments :

  1. I know you keep talking about the true meaning of the term "central dogma" being that info can't get out of proteins. That may be historically correct, but is it a useful distinction? Other people don't seem to think so. Plus we do need a shorthand name for "DNA to RNA to protein." Do you have a suggestion?

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    1. What you are talking about is the standard pathway of information flow with respect to protein-encoding genes.

      It doesn't apply to other genes.

      Why do we need a shorthand name for that?

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    2. "DNA to RNA to protein" seems pretty short to me. :)

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  2. Ted how about what Crick called it, the Sequence Hypothesis.

    It is a useful distinction at least for teaching purposes as it gets to the heart of the structure/function relationship. If you can answer that, you understand macromolecule structure/function and the underlying chemistry.

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  3. I've never really understood what the big deal is about the Central Dogma. It's a rather banal, trivial observation - whether it be Crick's version or not. I don't know why it's ever mentioned (except for historical interest).

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    1. Well, both the Sequence Hypothesis and the Central Dogma pertain to circumstances that are hardly banal or trivial. One shouldn't mistake knowledge which is easy to come by today for banality. It stands out as one of the greatest accomplishments of science - how a polymer of nucleotides that can be inherited is related to polymers of a very different monomer that makes possible that chemical phenomenon called life. Not to mention that researchers in the 50s, 60s, and 70s figured out all of the critical processes without any of the fancy kits and tools common in molecular biology labs today.

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    2. Yes, as I said, it's historically interesting. Otherwise I don't see the relevance of it. Why teach it as a core concept of molecular genetics? It falls out naturally itself and shouldn't require a special label.

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    3. Well I probably misread the intent of your comment, and jumped to the gun with the diatribe above. In fact I suspected that about 3 seconds after hitting reply.
      But I was reminded of one of my pet concerns, that too often topics like DNA replication, transcription and translation are taught as if they are trivial (perhaps even banal) topics that simply must be taught and rote memorized merely because they must be taught, and memorized, period. I've always felt that many a teacher misses the opportunity to invoke a sense in students of just how wonderous and amazing these fundamental processes really are. Anyway, as I say, a pet concern of mine.

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    4. If it "falls out" naturally then somehow its significance seems to have escaped many of the people who should know better. Crick no doubt thought it was natural when he first formulated it, but he still found it necessary to clarify what he meant in 1970, as he found too many people were misunderstanding it. (It seems hardly necessary to add that what Crick said it meant was what Larry says it means.) As long as there are people like James Shapiro who argue that exceptions are possible it remains a necessary term.

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  4. I have my doubts that people will get The Central Dogma correct. I also have doubts that transcriptional control is the most important factor in controlling protein levels in cells but that's another matter.
    I also have nearly resigned myself to people misusing the term "the Genetic Code" to mean genomic sequences.

    We need to do something and I have a suggestion. It's the You Owe Me a Beer suggestion.

    We create a website with a few key pages like www.youowemeabeer.org/centraldogma (and /geneticcode). The page explains the proper use of the term and a few examples of improper use. It also includes a note about why somebody should buy us a beer for enlightening them regards proper usage. We cognoscenti print out business cards with "You owe me a beer" www.youowemeabeer.org/centraldogma plus our contact information. When we witness misuse of a term (also known as a violation of all that is sacred), we present our card, perhaps with a very short note about the context of the violation. And maybe we at least get a beer now and then to sooth our irritated sensibilities.

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  5. This explanation seems simplistic. The missing part is the proteasome.

    http://www.ncbi.nlm.nih.gov/pubmed/12738238

    Some proteins in the cell last for hours -> days, others, e.g. signalling proteins, are destroyed almost immediately after use.

    Am I missing something?

    ps http://book.bionumbers.org

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